Prostaglandins are known to play an important role in causing inflammation. Prostaglandins are produced from arachidonic acid by cyclooxygenase (hereinafter abbreviated as “COX”). The activity of COX is suppressed to inhibit the synthesis of prostaglandins, particularly, PGE2, PGG2, and PGH2, resulting in the treatment of inflammation.
Two COX isoenzymes, COX-1 and COX-2, are known. COX-1 is inherently found in the gastrointestinal tract and kidney and is assumed to maintain physiological homeostatic functions, including gastrointestinal integrity and renal functions. Inhibition of COX-1 activity may cause life-threatening toxicities, such as ulcers and hemorrhage in the gastrointestinal tract. In contrast, COX-2 is induced by inflammatory stimuli and is known to be responsible for the development of inflammation.
COX-2 inhibitors are assumed to possess a broad spectrum of therapeutic activities as well as anti-inflammatory, analgesic, and antipyretic activities. For example, inhibition of COX-2 is known to prevent the onset of cancers, particularly colorectal cancer [J. Clin. Invest., 99, 2254 (1997)], can apply to the treatment of chronic neurodegenerative diseases, such as Alzheimer's disease [Neurology, 48, 626 (1997)], and is also known to be useful in the reduction of infarct volume accompanied by a stroke [J. Neuroscience, 17, 2746 (1997)].
Conventional non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, ketoprofen, ibuprofen, piroxicam, and diclofenac, inhibit both COX-1 and COX-2 to show gastrointestinal toxicities together with anti-inflammatory efficacy. Furthermore, such NSAIDs have fatal toxicities, such as hemorrhage and ulcers, arising from the inhibition of COX-1, limiting their clinical use. Thus, selective COX-2 inhibitors are useful as therapeutic agents against inflammation and diseases accompanied by inflammation without causing gastrointestinal toxicities, which are common during long-term use of conventional NSAIDs.
4,5-Diaryl-3(2H)-furanone derivatives have recently been reported as selective inhibitors against COX-2 (Korean Patent No. 10-0495389). Prior to use the furanone derivatives to prepare pharmaceutical compositions, the present inventors have derived an optimum crystalline structure through a study on stability depending on crystalline forms, and the compositions are required to have high dissolution rate, good flowability, optimum mass variation, and improved content uniformity. Therefore, the present inventors have found that a specific furanone derivative meets the requirements. Based on this finding, the present inventors have succeeded in preparing a capsule formulation and a tablet formulation using a pharmaceutical composition including the furanone derivative and finally arrived at the present invention.